PROJECT SUMMARY/ABSTRACT The Clinical Core (CC) of the Arizona ADCC is a consortium of five recruitment sites providing catchment areas throughout the state that comprise a standardized unit under a single Clinical Core Director. Since its inception, the CC has had an over-arching interest in the study of preclinical Alzheimer's disease (AD) and the accelerated evaluation of AD prevention therapies. It includes a cohort of cognitively unimpaired and annually assessed APOE e4 homozygotes (HMs), heterozygotes, and non-carriers, and has led us to incorporate longitudinal UDS assessments in an independently funded genetically enriched Arizona APOE cohort. CC resources are used to adjudicate their progression to mild cognitive impairment (MCI) and dementia leading to CC enrollment and consent for enrollment into our Brain and Body Donation Program (BBDP). The CC has provided subjects, DNA, longitudinal cognitive data and blood samples to characterize the preclinical course and trajectories of cognitive decline in unimpaired persons at three levels of genetic risk for AD; it has supported our effort to characterize PET, MRI and cerebrospinal fluid (CSF) changes associated with preclinical AD using independent NIA, state and organizational funds. It includes Latino and Native American APOE4 carriers and non-carriers to clarify the relevance of our advances to these understudied populations. It has led to collaborative research in other groups at genetic risk for AD, including children, young adult APOE4 carriers, Colombian presenilin 1 (PSEN1) E280A mutation carriers from the world's largest autosomal dominant AD (ADAD) cohort, and Down syndrome patients. It has provided data to help inform the design, statistical power, and optimized endpoints for our Alzheimer's Prevention Initiative (API) and API's ADAD and APOE4 HM trials. The CC maintains a target of 500 participants at all stages of the aging-dementia spectrum including 350 normal controls, 50 patients with MCI, and 100 with AD and other forms of degenerative dementia. Embedded within these diagnostic categories are defined Latino and Native American cohorts. The CC capitalizes on our multi-institutional diagnostic consensus conference, centralized data management program, and close working relationships with each of the other Cores. All subjects undergo standardized diagnostic testing that: 1) fulfills strict entrance criteria; 2) includes demographic, historical, medical, neurological, psychiatric, neuropsychological, and genetic measures; 3) incorporates the NACC Uniform Data Set (UDS); and 4) employs culturally sensitive test procedures. Patients eligible for enrollment and those completing annual follow-up are discussed in a biweekly diagnostic consensus conference. All undergo APOE genotyping at entry, and an annual standardized neuropsychological battery of tests at all sites. All are offered enrollment in the Brain Donation Program for neuropathological confirmation of clinical diagnoses. Patient eligibility for and participation in ongoing research projects is tracked and reviewed on an ongoing basis.